The mechanisms of cell stress response as targets for therapy and chemoprotection

New approaches to forward genetics of cancer

Genetic determinants of Akt-induced transformation

Non-coding RNAs

Biography

Dr. Eugene Kandel joined the staff of Roswell Park Cancer Institute (RPCI) in 2007, as Assistant Member at the Department of Cell Stress Biology.

Dr. Kandel earned an MS degree with honors from the Moscow State University (Moscow, Russia) in 1992 and his PhD from the University of Illinois (Chicago, IL) in 1998. Previously, Dr. Kandel has worked as a Postdoctoral Fellow and a Research Assistant Professor at the University of Illinois at Chicago, and as a Project Scientist and a Staff Scientist at the Cleveland Clinic Foundation in Cleveland, OH. Dr. Kandel also is an Assistant Professor at the State University of New York at Buffalo and the director of Graduate Studies for the Molecular and Cellular Biophysics and Biochemistry Program (http://www.roswellpark.edu/mcbb).

Dr. Kandel's research interest is in the study of signaling pathways in normal and diseased cells. He has authored or co-authored more than 40 journal publications and book chapters. Dr. Kandel has received “Golden Standard” distinction from the US Department of Defense, “Era of Hope” breast cancer research program (1996), “Innovator” Award from the Cleveland Clinic Foundation (2004), and Howard Temin Award from the National Cancer Institute (2005).

Background

The mechanisms of resistance and sensitivity to ischemia-like conditions in normal and malignant cells.

Simultaneous shortage of nutrients and oxygen, as happens under ischemia, is an extremely stressful condition for a mammalian cell. Organ ischemia frequently leads to organ failure. For example, ischemia is a common cause of acute kidney injury, which, in turn, is a major contributor to human mortality and morbidity worldwide. Our recent work utilized an unbiased genetic screen to identify a set of ten genes whose inhibition can improve survival of kidney cells in ischemia-like conditions. The findings offer insights into the strategies to prevent injury to the kidney and, possibly, other organs and tissues. We are interested in understanding the molecular mechanisms that determine the roles of the discovered genes in stress response, as well as in expanding the list of possible therapeutic targets beyond the ten candidates from our initial screen. Importantly, the lack of nutrients and oxygen is also an important factor in cancer progression. We are exploring how the various tumor adaptations to such a microenvironmental stress affect the future clinical trajectory of the disease.

The mechanisms of resistance and sensitivity to the inhibitors of MAP kinase cascade in human cancer.

Abnormal activation of the MAP kinase cascade is a common oncogenic event in human malignancies. One of the frequently mutated components of this pathway is a protein kinase encoded by BRAF gene. The recognition of hyperactive BRAF as the driver of many malignancies led to the emergence of therapeutic strategies to suppress its activity. This had a big impact on the management of metastatic melanoma, where BRAF mutations are common and inhibition of BRAF significantly improves survival. Unfortunately, some tumors are unresponsive to these drugs, while others develop resistance in the course of the treatment. We have identified several additional proteins that determine the response of cells to BRAF inhibitors. We are exploring these proteins as the predictors of clinical outcomes and as additional therapeutic targets to enhance the efficacy of anti-BRAF therapy.

Protein kinase Akt as a determinant of stress-resistance and -sensitivity in normal and malignant cells.

Protein kinase B, also known as Akt, is а key regulator of many processes in normal cells. In cancer, Akt gets hyper-activated. This phenomenon contributes to enhanced survival, growth, genetic instability and many other characteristic traits of oncogenically transformed cells. Overall, constitutive activation of Akt is one of the most common biochemical abnormalities in human malignancies. Often, it is a sign of a more aggressive or advanced disease. Importantly, in order to act as an oncogene, Akt depends on cooperation with certain other cellular factors. Furthermore, constitutive activation of Akt is a very stressful event for a normal cell and requires additional adaptations to be tolerated. We are exploring specific dependencies and vulnerabilities associated with oncogenic activation of Akt. Our long-term goal is to use this information to selectively suppress or eliminate cancer cells while sparing normal tissues.